1. Field of Invention
The present invention relates to compounds having progesterone receptor binding inhibitory activity and pharmaceutical compositions containing the same.
2. Background Art
In recent years, also in Japan, there is a tendency for the number of patients suffering from breast cancer to increase, and it is foreseen that the number of patients suffering from breast cancer would become largest among the malignant tumors in women in the 21st century. Ovariectomy has for the first time been used as endocrinotherapy for breast cancer. Thereafter, adrenalectomy and hypophysectomy have been reported to be useful as therapy for breast cancer in progress, and, since then, surgical endocrinotherapy has been mainly used and made progress. In the surgical endocrinotherapy, an organ involved in the secretion of estrogen is removed to regress estrogen dependent breast cancer. This, however, results in loss of not only estrogen but also life-sustaining hormones, including steroid hormones, posing many problems associated with the quality of life.
Non-steroidal anti-estrogen agents typified by Tamoxifen Citrate which appeared in the latter half of 1970s, by virtue of high effect against breast cancer and much lower side effect than conventional androgen and estrogen, have become extensively applied in clinical investigations and replaced the surgical endocrinotherapy used as main therapy for breast cancer up to that point.
More recently, agents having a new mechanism of action, such as medroxyprogesterone acetate (MPA) ("NYUGAN NO RINSHO", vol. 1, 201-213 (1986)), aromatase inhibitor, luteinizing hormone releasing hormone (LH-RH) agonist ("GAN TO KAGAKU RYOHO", 16, 2729 (1994)) have been developed, resulting in diversified endocrinotherapy for breast cancer.
On the other hand, the treatment of breast cancer with an antiprogesterone agent based on progesterone receptor has been actively attempted particularly in recent years. For example, Mifepristone (RU38486) (FR2497807), Onapristone (ZK98299) (DE3321826) are under development.
Since, however, all of them have a steroidal skeleton, they have been pointed out to have side effect characteristic of steroid. Therefore, in order to overcome these problems, the appearance of an agent having progesterone receptor binding inhibitory activity without the steroid skeleton has been desired in the art.
The present inventors have previously succeeded in isolation of substance PF1092, having inhibitory activity against binding of progesterone to progesterone receptor, from a cultured mixture of a strain belonging to the genus Penicillium (Japanese Patent Application Nos. 20860/1995 and 17074/1996 and EP96100580.8, which are incorporated herein by reference).